Action Points

Off-label transcatheter aortic valve replacement (TAVR) was associated with higher in-hospital, 30-day, and 1-year mortality rates compared with on-label TAVR use, but after adjustment, 1-year mortality was similar in the two groups.

Note that approximately one in 10 TAVR patients in the United States have received the procedure for an off-label indication.

Off-label transcatheter aortic valve replacement (TAVR) procedures were associated with more in-hospital adverse events and 30-day mortality, although 1 year outcomes were similar to on-label use, the national Transcatheter Valve Therapy (TVT) Registry showed.

TAVR done in patients with severe regurgitation, low surgical risk, and other scenarios not approved by the FDA accounted for 9.5% of TAVR done in the U.S. from 2011 to 2014, Ravi S. Hira, MD, of University of Washington in Seattle, and colleagues reported in JAMA Cardiology.

Three-quarters of off-label indications were deemed so due to presence of severe aortic or mitral regurgitation or both; one-fifth were off-label because of bicuspid valves.

In the unadjusted analysis, off-label TAVR was associated with a survival disadvantage both at 30 days (8.5% versus 6.1%; P<0.001) and 1 year (25.6% versus 22.1%; P=0.001). After adjustment, 30-day mortality remained higher in the off-label group (HR 1.27, 95% CI 1.04-1.55) but the 1-year difference dissipated (HR 1.11, 95% CI 0.98-1.25;).

Mortality was most likely for patients with severe mitral regurgitation as the only off-label indication for TAVR. The authors suggested this is owing to secondary mitral regurgitation caused by left ventricular dilatation.

"Our study indicates a need for further evaluation of TAVR in off-label indications to inform decisions for patients who were excluded from the initial trials," the authors suggested. "Off-label use implies that a therapy has not been studied in certain populations or for certain indications. It does not necessarily imply that therapy is inappropriate or ineffective for these patients."

In the meantime, they wrote, their data suggest "acceptable results" with off-label TAVR -- despite the TVT Registry not having data for surgery or medical therapy for comparison.

Missing pieces in the evidence base for TAVR and other evolving technologies is a major reason why the FDA is pushing for faster accrual of high-quality device data, according to Robert M. Califf, MD, of Duke University School of Medicine in Durham, N.C., and former FDA Commissioner.

"Under the envisioned system, simultaneous evaluation for marketing and payment is possible, and demonstration projects have been promising. Amid all of this optimism, however, it is critical to remember that these devices are expensive and that health systems and payers should demand evidence of a favorable benefit/risk balance," he wrote in an accompanying editorial.

Califf suggested that such a system would benefit most parties: "Inventors and device manufacturers will see reductions in development and evaluation costs, while clinicians, the FDA, and CMS [Centers for Medicare & Medicaid Services] will have higher-quality evidence to inform decision making at the individual and population levels."

"Most importantly, patients will have confidence that they are receiving beneficial device procedures in the context of high-quality clinical care," he said.

A second accompanying editorial also expressed interest in overhauling the system of clinical evidence-gathering.

"Taken together, the strengths and weaknesses of the Hira et al study and the TVT Registry represent an opportunity to reconsider tools used by the FDA and CMS to incentivize evidence generation," wrote Karen E. Joynt, MD, MPH, and Daniel B. Kramer, MD, MPH, both of Boston's Harvard Medical School.

"Expanding data collection to not just device recipients but to all patients referred for consideration for undergoing a TAVR, for example, could be explored as a way to capture more robust comparative effectiveness data and truly drive transformative advances in knowledge," the pair suggested.

The TVT Registry identified 23,847 patients who got TAVR with Sapien and CoreValve devices at 328 hospitals. CMS records containing outcomes data were linked for 15,397. Off-label TAVR was defined as use in patients with known bicuspid valve, moderate aortic stenosis (mean gradient <40 mm Hg and valve area >1 cm2 when left ventricular systolic function is >55%), severe mitral or aortic regurgitation prior to the procedure, or subaortic stenosis.

Median age was 84 years among all TAVR recipients, and half were men. Off-label TAVR was more likely to be performed in patients with:

Hira and colleagues acknowledged that varying interpretations of regurgitation severity are possible between operators, and that they were unable to use the TVT Registry to compare TAVR patients with peers getting surgery or medical therapy for their aortic stenosis.

Hira had no conflicts of interest listed.

Co-authors reported multiple relationships with industry.

Califf receives consulting fees from Merck and is employed with Verily Life Sciences. Previously, he has received research grant funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, the US Food and Drug Administration, Amylin, and Eli Lilly and Company; research grants and consulting fees from Bristol-Myers Squibb, Janssen Research and Development, Merck, and Novartis; consulting fees from Amgen, Bayer Healthcare, BMEB Services, Genentech, GlaxoSmithKline, Daiichi Sankyo, Kowa, Les Laboratoires Servier, Medscape/Heart.org, Regado, and Roche; and he also held equity in N30 Pharma and Portola.

Joynt reported getting fees for contract work for the Office of the Assistant Secretary for Planning and Evaluation of the U.S. Department of Health and Human Services.

Kramer disclosed consulting fees from the Circulatory Systems Advisory Panel of the FDA and the Baim Clinical Research Institute for clinical trials of medical devices.

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